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mortality&#44; exacerbations&#44; cardiac adverse event&#44; and serious adverse event &#40;SAE&#41; outcomes of patients from Latin American geographical region versus RoW in the TIOSPIR<span class="elsevierStyleSup">&#174;</span> trial&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Study design</span><p id="par0020" class="elsevierStylePara elsevierViewall">TIOSPIR<span class="elsevierStyleSup">&#174;</span> &#40;<a id="intr0005" class="elsevierStyleInterRef" href="https://clinicaltrials.gov/NCT01126437">NCT01126437</a>&#41; was a large &#40;<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>17<span class="elsevierStyleHsp" style=""></span>135&#41;&#44; long-term &#40;2&#8211;3-year&#41;&#44; randomized&#44; double-blind&#44; parallel-group&#44; double-dummy&#44; event-driven trial in patients with COPD comparing the safety and efficacy of once-daily tiotropium &#40;SPIRIVA<span class="elsevierStyleSup">&#174;</span> &#91;Boehringer Ingelheim&#44; Ingelheim am Rhein&#44; Germany&#93;&#41; via Respimat<span class="elsevierStyleSup">&#174;</span> 5<span class="elsevierStyleHsp" style=""></span>&#956;g &#40;2 inhalations of 2&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g&#41;&#44; and 2&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g &#40;2 inhalations of 1&#46;25<span class="elsevierStyleHsp" style=""></span>&#956;g&#41;&#44; or via HandiHaler<span class="elsevierStyleSup">&#174;</span> 18<span class="elsevierStyleHsp" style=""></span>&#956;g&#59; 17<span class="elsevierStyleHsp" style=""></span>116 patients constituted the as-treated population and were included in this analysis&#46; The study design&#44; detailed methods&#44; and primary results were published previously&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">12&#44;14</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Study population</span><p id="par0025" class="elsevierStylePara elsevierViewall">All participants had a confirmed diagnosis of COPD &#40;forced expiratory volume in 1 second &#91;FEV<span class="elsevierStyleInf">1</span>&#93; &#8804;70&#37; predicted and FEV<span class="elsevierStyleInf">1</span>&#47;forced vital capacity &#8804;0&#46;70&#41;&#44; were aged &#8805;40 years&#44; and had &#8805;10 pack-years of smoking history&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> Patients with concomitant cardiac diseases were included in the study&#44; except those with recent &#40;&#8804;6 months&#41; myocardial infarction &#40;MI&#41;&#44; severe arrhythmia&#44; or a change in drug therapy within the previous year&#59; or hospitalization for cardiac failure within the previous year&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> All usual background treatments for COPD&#44; except other inhaled anticholinergics&#44; were allowed&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The geographical region of Latin America enrolled patients in Argentina&#44; Brazil&#44; Colombia&#44; Guatemala&#44; Mexico&#44; Panama&#44; and Peru&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Outcome measures</span><p id="par0035" class="elsevierStylePara elsevierViewall">Outcomes of interest in this analysis were time to all-cause death&#44; time to first moderate-to-severe or severe exacerbation&#44; time to major adverse cardiovascular events &#40;MACE&#41; and fatal MACE&#44; and SAEs for patients in Latin America versus RoW&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Assessments</span><p id="par0040" class="elsevierStylePara elsevierViewall">An independent mortality adjudication committee&#44; blinded to treatment assignments attributed the cause of each death&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> Non-fatal stroke and MI &#40;included in MACE&#41; were reported by study investigators and verified for classification accuracy by central reviewers who were blinded to treatment assignment&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Exacerbations were defined as the worsening of &#8805;2 major respiratory symptoms &#40;dyspnoea&#44; cough&#44; sputum&#44; chest tightness&#44; or wheezing&#41; for &#8805;3 days and requiring specified treatment changes&#46; Moderate-to-severe exacerbations required a prescription for antibiotics&#44; systemic corticosteroids&#44; or both &#40;with no hospitalization&#41;&#59; severe exacerbations required hospitalization&#46; The onset of exacerbation was defined as the onset of the first recorded symptom&#59; the end of exacerbation was decided by the investigator&#44; based on clinical judgment&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">A composite endpoint of MACE was included in the analyses&#44; comprising stroke&#44; transient ischaemic attack &#40;TIA&#41;&#44; MI&#44; sudden death&#44; cardiac death&#44; sudden cardiac death&#44; or fatal event in the system organ classes &#40;SOCs&#41; for cardiac and vascular disorders&#46; SOCs were defined according to the Medical Dictionary for Regulatory Activities standardizing attributions of AEs globally&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0055" class="elsevierStylePara elsevierViewall">Based on similar efficacy and safety results among the tiotropium treatment arms in the primary analysis&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">12</span></a> data were pooled for this post-hoc exploratory analysis&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Baseline characteristics discriminating between patients in Latin America and RoW were identified and compared descriptively&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Hazard ratios &#40;HRs&#41; and 95&#37; confidence intervals &#40;CIs&#41; for time to events by region were calculated using a Cox proportional hazards regression model without covariate adjustment&#44; and displayed via Kaplan&#8211;Meier plots&#46; A negative binomial regression model was used to estimate the number of exacerbations&#46; HRs for time to death and time to moderate-to-severe exacerbation analyses&#44; by region and baseline characteristics&#44; are shown as forest plots&#46; Additional analyses of time to death and moderate-to-severe exacerbation&#44; severe exacerbations&#44; and MACE were adjusted for covariates including age&#44; post-bronchodilator FEV<span class="elsevierStyleInf">1</span>&#37; predicted&#44; gender&#44; exacerbation history&#44; smoking history &#40;pack-years&#41;&#44; body mass index &#40;BMI&#41;&#44; and history of cardiac disorders&#44; MI&#44; coronary artery disease&#47;ischaemic heart disease &#40;CAD&#47;IHD&#41;&#44; cardiac arrhythmia&#44; heart failure &#40;class I&#8211;IV&#41;&#44; and stroke&#47;TIA&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">Incidence rates&#44; incidence rate ratios &#40;IRRs&#41;&#44; and 95&#37; CIs for causes of death were calculated&#46; SAEs are provided in the Supplementary Material&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">For the mortality analysis &#40;vital status&#41;&#44; data were included if death occurred up until the study end date&#44; irrespective of treatment discontinuation&#46; For the exacerbation analysis &#40;on-treatment&#41;&#44; events were counted from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 day&#44; and for MACE to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>30 days&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Study population</span><p id="par0080" class="elsevierStylePara elsevierViewall">Of the TIOSPIR<span class="elsevierStyleSup">&#174;</span> population&#44; 1000 patients from Latin America and 16<span class="elsevierStyleHsp" style=""></span>116 patients from RoW were included &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Total exposure to tiotropium was 1855 and 32<span class="elsevierStyleHsp" style=""></span>229 patient-years for Latin America and RoW&#44; respectively&#46; A total of 228 &#40;22&#46;8&#37;&#41; patients from Latin America and 3689 &#40;22&#46;9&#37;&#41; patients from RoW discontinued prematurely from trial medication&#46; Reasons for premature discontinuation were similar&#44; and mainly due to AEs&#44; with respiratory disorders &#40;including COPD&#41; being the most common AEs&#44; followed by neoplasms&#44; and infections and infestations&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">12</span></a> Vital status follow-up was complete for 99&#46;1&#37; and 99&#46;8&#37; of patients from Latin America and RoW&#44; respectively&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Baseline characteristics</span><p id="par0085" class="elsevierStylePara elsevierViewall">At baseline&#44; patients enrolled in Latin America were comparatively older &#40;higher proportion of patients aged &#8805;70 years&#41;&#44; and had higher mean pack-years of smoking history than those in RoW&#44; although a lower percentage were current smokers &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; A higher proportion of patients in Latin America had COPD exacerbation in the year prior to the trial than those in RoW&#46; Latin American patients were more likely to have very severe COPD &#40;Global Initiative for Chronic Obstructive Lung Disease &#91;GOLD&#93; Stage IV&#41; versus RoW &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Fewer Latin American patients had a history of cardiac disorders&#44; or were receiving cardiovascular medication at baseline versus RoW &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The proportions of patients receiving long-acting muscarinic antagonist &#40;LAMA&#41; or long-acting &#946;<span class="elsevierStyleInf">2</span>-agonist &#40;LABA&#41; at baseline were lower in Latin America than in RoW&#59; however&#44; they were more likely to receive inhaled corticosteroids &#40;ICS&#41; &#40;with or without LABA&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Mortality</span><p id="par0090" class="elsevierStylePara elsevierViewall">During the study&#44; a greater proportion of patients died in the Latin American population &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>100 &#91;10&#46;0&#37;&#93;&#41; versus RoW &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1200 &#91;7&#46;4&#37;&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>A&#41;&#46; Analysis of time to death confirmed that patients in Latin America had a higher risk of death than those in RoW &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;52 &#91;1&#46;24&#8211;1&#46;86&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>A&#59; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; This was also true when the analysis of time to death was adjusted for age&#44; gender&#44; FEV<span class="elsevierStyleInf">1</span>&#37; predicted&#44; exacerbation history&#44; smoking history &#40;pack-years&#41;&#44; BMI&#44; history of cardiac disorders&#44; MI&#44; CAD&#47;IHD&#44; cardiac arrhythmia&#44; heart failure &#40;class I&#8211;IV&#41;&#44; and stroke&#47;TIA &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;37 &#91;1&#46;11&#8211;1&#46;69&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>A&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">While the overall risk of death was increased in patients from Latin America versus RoW&#44; regression analysis according to baseline characteristics showed that the risk of death was similar for Latin America and RoW in patients with BMI &#8805;30<span class="elsevierStyleHsp" style=""></span>kg&#47;m<span class="elsevierStyleSup">2</span> &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;07 &#91;0&#46;58&#8211;1&#46;96&#93;&#41;&#44; and patients with cardiac arrhythmia &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;06 &#91;0&#46;62&#8211;1&#46;82&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; The largest HRs were observed in patients with GOLD Stage IV &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;87 &#91;1&#46;26&#8211;2&#46;77&#93;&#41; and in those who received LABA &#40;but no ICS&#41; &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;94 &#91;1&#46;05&#8211;3&#46;60&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#44; however the LABA &#40;no ICS&#41; result is based on small patient number&#46; Causes of death were mainly similar between the regions&#44; except for respiratory&#44; thoracic&#44; and mediastinal disorders&#44; including COPD&#44; gastrointestinal disorders&#44; general disorders including death due to unknown reason &#40;sudden cardiac death and death&#41;&#44; and infections and infestations&#44; where the incidence rate was higher in the Latin American region versus RoW&#46; General disorders&#44; neoplasms&#44; and respiratory disorders&#44; including COPD&#44; contributed the majority of deaths &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">COPD exacerbations</span><p id="par0100" class="elsevierStylePara elsevierViewall">Similar to the mortality analysis&#44; the risk of moderate-to-severe exacerbation &#40;time to first moderate-to-severe exacerbation&#41; was higher in patients in Latin America versus RoW &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;29 &#91;1&#46;18&#8211;1&#46;41&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>B&#59; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; Additional analysis adjusting for relevant covariates confirmed a higher risk of moderate-to-severe exacerbations in Latin American patients versus RoW &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;13 &#91;1&#46;03&#8211;1&#46;23&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>B&#41;&#46; Accordingly&#44; the annual rate of moderate-to-severe exacerbations was higher in Latin America &#40;RR &#91;95&#37; CI&#93;&#58; 1&#46;25 &#91;1&#46;13&#8211;1&#46;38&#93;&#41; even when adjusted for covariates &#40;RR &#91;95&#37; CI&#93;&#58; 1&#46;07 &#91;0&#46;97&#8211;1&#46;18&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>B&#41;&#46; Time to first moderate-to-severe exacerbation according to baseline characteristics confirmed the increased risk in Latin America versus RoW&#44; except for patients receiving LABA &#40;but no ICS&#41; at baseline &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;06 &#91;0&#46;77&#8211;1&#46;47&#93;&#41;&#44; where the risk was similar between both regions &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; In contrast&#44; patients in Latin America had a lower risk of severe COPD exacerbation &#40;longer time to first severe exacerbation leading to hospitalization&#41; &#40;HR &#91;95&#37; CI&#93;&#58; 0&#46;82 &#91;0&#46;68&#8211;0&#46;98&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>C&#59; <a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#41;&#44; including when adjusted for covariates &#40;HR &#91;95&#37; CI&#93;&#58; 0&#46;67 &#91;0&#46;55&#8211;0&#46;81&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>C&#41;&#46; Severe exacerbations also occurred less frequently versus RoW &#40;RR &#91;95&#37; CI&#93;&#58; 0&#46;76 &#91;0&#46;61&#8211;0&#46;94&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>C&#41;&#44; and similar results were obtained when adjusted for covariates &#40;RR &#91;95&#37; CI&#93;&#58; 0&#46;62 &#91;0&#46;50&#8211;0&#46;77&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>C&#41;&#46; Time to first severe exacerbation according to baseline characteristics adjusted for covariates supported the lower risk of severe exacerbation in Latin American patients versus RoW&#44; except for patients receiving ICS &#40;but no LABA&#41; at baseline &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;01 &#91;0&#46;63&#8211;1&#46;63&#93;&#41; and patients with cardiac arrhythmia &#40;HR &#91;95&#37;CI&#93;&#58; 1&#46;07 &#91;0&#46;68&#8211;1&#46;66&#93;&#41;&#46; However&#44; an increased risk of severe exacerbations was observed in underweight &#40;BMI<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>18&#46;5&#41; patients in Latin America versus RoW &#40;HR &#91;95&#37;CI&#93;&#58; 1&#46;30 &#91;0&#46;79&#8211;2&#46;12&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 6</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Time to first MACE and SAEs</span><p id="par0105" class="elsevierStylePara elsevierViewall">The risk of MACE &#40;HR &#91;95&#37; CI&#93;&#58; 0&#46;99 &#91;0&#46;71&#8211;1&#46;40&#93;&#41; was similar between Latin America and RoW &#40;<a class="elsevierStyleCrossRef" href="#fig0035">Fig&#46; 7</a>&#41; even when adjusted for covariates &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;01 &#91;0&#46;71&#8211;1&#46;42&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>D&#41;&#46; However&#44; the risk of fatal MACE &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;41 &#91;0&#46;93&#8211;2&#46;13&#93;&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>D&#41; was numerically higher in Latin America versus RoW&#44; although only a small proportion of patients had fatal MACE &#40;2&#46;4&#37; in Latin America vs 1&#46;9&#37; in RoW&#59; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>D&#41;&#46;</p><elsevierMultimedia ident="fig0035"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Incidence rates of SAEs were lower in Latin America than in the RoW&#44; including cardiac disorders&#44; cancer&#44; nervous system disorders&#44; and overall respiratory disorders including COPD &#40;Table S1&#41;&#46;</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Discussion and conclusions</span><p id="par0115" class="elsevierStylePara elsevierViewall">Latin America is undergoing demographic changes characterized by increased ageing of the population&#44; and the higher proportion of patients aged &#8805;60 years in Latin American countries is a reflection of this statistic&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">7&#44;15</span></a> As expected&#44; Latin American patients also had higher pack-years of smoking history versus RoW&#44; although current smokers were less frequent in Latin America&#44; indicating that more patients had stopped smoking prior to study start&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Compared with RoW&#44; more patients in Latin America had very severe COPD &#40;GOLD Stage IV&#41; at baseline&#44; possibly indicating that these patients remained undiagnosed during the early stages of COPD&#44; and reflecting suboptimal disease management in this region&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">15&#44;16</span></a> The PLATINO study&#44; identified underdiagnosis as an issue across Latin America&#44;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">17</span></a> while more than half of patients included in the PUMA study were not using bronchodilators&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">18</span></a> Our findings support this earlier research&#44; with few patients using bronchodilators at baseline&#44; suggesting a significant gap between guideline recommendations and prescribing patterns in this region&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">18</span></a> A scarcity of respiratory specialists and training programmes in many Latin American countries<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">7</span></a> is likely to increase the risk of poor clinical outcomes&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">10</span></a> These factors could also have contributed to the observed higher proportion of patients with exacerbations in the year prior to our study&#46; Thorough assessment&#44; accurate diagnosis&#44; and prompt initiation of management strategies &#40;such as smoking cessation and maintenance respiratory therapy&#41; in COPD are known to be essential for mitigating future risks&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">7&#44;10&#44;15</span></a> Evidence-based literature recommends smoking cessation at early stages of COPD&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">19</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Latin American patients had increased risk of death compared with RoW&#44; even when adjusted for age&#44; gender&#44; FEV<span class="elsevierStyleInf">1</span>&#37; predicted&#44; exacerbation history&#44; smoking history &#40;pack-years&#41;&#44; BMI&#44; and history of cardiac disorders&#44; MI&#44; CAD&#47;IHD&#44; cardiac arrhythmia&#44; heart failure &#40;class I&#8211;IV&#41;&#44; and stroke&#47;TIA&#46; These factors are proposed drivers of mortality and morbidity in COPD<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">10&#44;20&#44;21</span></a> and are likely to be relevant regardless of geographical location&#46; Findings from the PLATINO study also support an association between COPD and increased mortality when adjusted by age&#44; smoking status&#44; pack-years smoking&#44; quality of life&#44; BMI&#44; and comorbidities&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">4</span></a> Comparable with previous findings&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">4</span></a> the incidence rate of death due to respiratory&#44; thoracic&#44; and mediastinal disorders&#44; including COPD&#44; was higher in Latin America versus RoW in our study&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Latin American patients also had a higher risk of moderate-to-severe exacerbation than patients in RoW&#46; The risk was consistently higher in most subgroups&#44; except for patients receiving LABA &#40;but not ICS&#41; at baseline&#46; Nevertheless&#44; although Latin American patients presented with more severe disease at baseline&#44; and higher mortality or moderate-to-severe exacerbation risks&#44; our analysis demonstrated that they were less likely to have severe exacerbation than RoW&#46; This was true even when the analysis was adjusted for covariates&#44; except for patients receiving ICS at baseline and patients with cardiac arrhythmia&#59; underweight patients had an increased risk in Latin America versus RoW&#46; Fewer severe exacerbations were recorded as a result of the scarcity of admission beds<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">22</span></a> in Latin American hospitals&#44; or related healthcare challenges such as inadequate facilities for critical care units&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">7</span></a> Our findings were contrary to those of several Latin American epidemiology studies&#44; which found that hospitalization due to exacerbation was commonplace&#44; reflecting undertreatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">15&#44;16&#44;18</span></a> In the PUMA study&#44; frequent overtreatment with corticosteroids was observed in patients without an exacerbation in the past year&#44; while a lower hospitalization rate was not deemed to support the extensive use of corticosteroids&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">16</span></a> Our results showed that corticosteroid overuse was prevalent in Latin America&#44; as more patients were likely to receive ICS at baseline versus RoW&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Unlike the regional differences we identified for Latin American patients&#44; the TIOSPIR<span class="elsevierStyleSup">&#174;</span> subanalysis of an Asian cohort observed similar mortality rates in Asian patients versus RoW patients&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a> Further&#44; Asian patients reported fewer exacerbations than those in RoW&#44; whereas the proportion with a severe exacerbation was higher&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a> This may be attributed to differences in the healthcare system in different regions&#59; for example&#44; in Asia&#44; patients are frequently hospitalized for an exacerbation due to non-availability of corticosteroids or antibiotics in a primary healthcare unit&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a> The observed discrepancies between the results for the Asian and the Latin American cohort illustrate how racial and&#47;or geographical differences can impact hospitalization rates and treatment outcomes in COPD trials&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Patients enrolled in TIOSPIR<span class="elsevierStyleSup">&#174;</span> in Latin America were less likely to have a history of cardiac disorders or to be receiving cardiovascular medications at baseline compared with RoW&#46; Assuming that their initial cardiovascular comorbidity was indeed lower&#44; it is therefore rational that Latin American patients were less likely to experience a cardiac disorder SAE than those in RoW during the trial&#46; The composite outcome of MACE was actually similar for both regions&#44; though the risk of fatal MACE was numerically increased in Latin American patients&#46; Further research is needed to clarify relative cardiac risks in this cohort&#44; and the predisposing factors&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">It was beyond the scope of our analysis to assess differences in baseline characteristics and outcomes between individual countries in the Latin American region&#44; as the sample sizes may be too small to enable meaningful assessment&#46; Environmental factors not assessed here also influence COPD-related risks&#44; such as access to healthcare and alternative disease management strategies&#44;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">7&#44;23&#8211;25</span></a> the extent of solid fuel use&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">10</span></a> or living at high altitude&#46; Hypoxia can have unwanted extra pulmonary systemic effects in patients with COPD&#44; and might be associated with high altitude and mortality from COPD&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">26</span></a> Temperature inversions can also result in a buildup of air pollution that is detrimental to those with respiratory conditions&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">27</span></a> In addition&#44; patients with COPD in tropical countries &#40;such as Brazil&#44; Columbia&#44; and Peru&#41; may be particularly prone to exacerbations&#44; as infections are more prevalent throughout the year&#44; and not just in the winter months &#40;owing to the high humidity and lack of seasonal variation in temperature&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">28</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">The large population size and 2- to 3-year duration of the TIOSPIR<span class="elsevierStyleSup">&#174;</span> trial&#44; along with the wide range of nationalities included &#40;50 countries across different regions of the world<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a>&#41;&#44; constitute strengths of this analysis&#46; Patients in TIOSPIR<span class="elsevierStyleSup">&#174;</span> constituted a convenience sample from 7 Latin American countries &#40;rather than a sample representative of the whole population&#41; and should therefore be interpreted with caution if generalized to Latin America overall&#46; However&#44; the patient characteristics are representative of the patients seen in specialist practice globally&#44; and the continuation of regular maintenance respiratory medication and inclusion of patients with cardiac disease ensured that the population reflects real-world patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">12&#44;14</span></a> Thus&#44; we feel that the results are likely to be valid in a clinical setting&#46; However&#44; as this was a post-hoc rather than a predefined subgroup analysis&#44; it is not possible to confirm the reasons why outcome risks differed between Latin America and RoW&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Latin American patients with COPD in TIOSPIR<span class="elsevierStyleSup">&#174;</span> had a higher risk of death and COPD exacerbations versus RoW patients&#44; but were less likely to be hospitalized for an exacerbation&#46; The prevalence of tobacco smoking&#44; exposure to environmental contaminants&#44; or healthcare challenges might impact treatment outcomes and lead to different results for patients enrolled from various regions in international trials of COPD&#46; This should be considered when designing trials and evaluating the global clinical relevance of the results&#46; Further studies should explore factors influencing the increased risk of mortality in Latin America compared with RoW&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Funding</span><p id="par0160" class="elsevierStylePara elsevierViewall">The TIOSPIR<span class="elsevierStyleSup">&#174;</span> trial and this post-hoc study were funded by Boehringer Ingelheim&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Authorship</span><p id="par0165" class="elsevierStylePara elsevierViewall">All authors confirm involvement in the conception&#44; hypotheses delineation&#44; and design of the study&#59; acquisition&#44; analysis&#44; or interpretation of the data&#59; writing or substantial involvement in the article&#39;s revision prior to submission&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflict of interest</span><p id="par0170" class="elsevierStylePara elsevierViewall">AA reports receiving consulting fees&#44; lecture fees&#44; or travel support from AstraZeneca&#44; Boehringer Ingelheim&#44; Forest Laboratories&#44; GlaxoSmithKline&#44; and Novartis&#46; PMAC has received research grants from GlaxoSmithKline and Takeda&#59; personal fees from AstraZeneca&#44; Boehringer Ingelheim&#44; GlaxoSmithKline&#44; Novartis&#44; and Takeda&#59; and non-financial support from Boehringer Ingelheim&#46; AM&#44; NM&#44; and MH are employees of Boehringer Ingelheim&#46; JRJ reports receiving consulting fees&#44; lecture fees&#44; or travel support from AstraZeneca&#44; Boehringer Ingelheim&#44; Novartis&#44; Grifols&#44; CSL&#44; Zambon&#44; EMS&#44; and Chiesi in the past 12 months&#46; EP reports receiving consulting fees&#44; lecture fees&#44; or travel support from Ache&#44; AstraZeneca&#44; Boehringer Ingelheim&#44; GlaxoSmithKline&#44; Novartis&#44; and Chiesi in the past 12 months&#59; EP is currently a Global Medical Expert for GlaxoSmithKline&#46; HG is an advisory member of Boehringer Ingelheim&#44; Novartis&#44; GSK&#44; AstraZeneca&#44; and Mundipharma&#59; and has received lecture fees from Novartis&#44; and travel support from MSD and AstraZeneca&#46; ARV reports travel support from AstraZeneca and Novartis in the past 12 months&#46; ERG reports receiving travel support&#44; consulting fees and lecture fees from GlaxoSmithKline&#44; AstraZeneca&#44; Boehringer Ingelheim and Mundipharma&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Geographical variations may impact outcomes in chronic obstructive pulmonary disease &#40;COPD&#41;&#46; We evaluated differences in baseline characteristics and outcomes between patients enrolled in Latin America compared with the rest of the world &#40;RoW&#41; in the TIOtropium Safety and Performance In Respimat<span class="elsevierStyleSup">&#174;</span> &#40;TIOSPIR<span class="elsevierStyleSup">&#174;</span>&#41; trial&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">TIOSPIR<span class="elsevierStyleSup">&#174;</span>&#44; a 2&#8211;3-year&#44; randomized&#44; double-blind trial &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>17<span class="elsevierStyleHsp" style=""></span>116&#59; treated set&#41;&#44; compared safety and efficacy of once-daily tiotropium Respimat<span class="elsevierStyleSup">&#174;</span> 5 and 2&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g with tiotropium HandiHaler<span class="elsevierStyleSup">&#174;</span> 18<span class="elsevierStyleHsp" style=""></span>&#956;g&#46; This post-hoc analysis pooled data from all treatment arms to assess mortality&#44; exacerbations&#44; cardiac events&#44; and serious adverse events &#40;SAEs&#41; between both regions&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">At baseline&#44; patients enrolled in Latin America &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1000&#41; versus RoW &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>116&#41; were older&#44; with higher pack-years of smoking history and more exacerbations&#44; but less cardiac history&#46; In this analysis&#44; patients in Latin America versus RoW had an increased risk of death &#40;hazard ratio &#91;HR&#93; &#91;95&#37; confidence interval &#40;CI&#41;&#93;&#58; 1&#46;52 &#91;1&#46;24&#8211;1&#46;86&#93;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&#41; or moderate-to-severe exacerbation &#40;HR &#91;95&#37; CI&#93;&#58; 1&#46;29 &#91;1&#46;18&#8211;1&#46;41&#93;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&#41;&#44; but a lower risk of severe exacerbation &#40;HR &#91;95&#37; CI&#93;&#58; 0&#46;82 &#91;0&#46;68&#8211;0&#46;98&#93;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0333&#41;&#46; SAE rates in Latin America were lower versus RoW &#40;incidence rate ratio &#91;IRR&#93; &#91;95&#37; CI&#93;&#58; 0&#46;82 &#91;0&#46;72&#8211;0&#46;92&#93;&#41;&#44; including cardiac disorders &#40;IRR &#91;95&#37; CI&#93;&#58; 0&#46;68 &#91;0&#46;48&#8211;0&#46;97&#93;&#41;&#46; Risk of major adverse cardiovascular events were similar &#40;HR &#91;95&#37; CI&#93;&#58; 0&#46;99 &#91;0&#46;71&#8211;1&#46;40&#93;&#59; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;9677&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">TIOSPIR<span class="elsevierStyleSup">&#174;</span> patients in Latin America had a higher risk of death or moderate-to-severe exacerbation&#44; but a lower risk of severe exacerbation than those in RoW&#46; Geographical differences may impact outcomes in COPD trials&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Las variaciones geogr&#225;ficas pueden afectar a los resultados en la enfermedad pulmonar obstructiva cr&#243;nica &#40;EPOC&#41;&#46; Evaluamos las diferencias en las caracter&#237;sticas basales y los resultados de los pacientes incluidos en Latinoam&#233;rica en comparaci&#243;n con el resto del mundo &#40;RdM&#41; en el ensayo <span class="elsevierStyleItalic">TIOtropium Safety and Performance In Respimat</span><span class="elsevierStyleSup">&#174;</span> &#40;TIOSPIR<span class="elsevierStyleSup">&#174;</span>&#41;&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">TIOSPIR<span class="elsevierStyleSup">&#174;</span>&#44; es un estudio aleatorizado&#44; doble ciego de 2-3 a&#241;os de duraci&#243;n &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>17&#46;116&#59; conjunto tratado&#41;&#44; compar&#243; la seguridad y la eficacia del tiotropio Respimat<span class="elsevierStyleSup">&#174;</span> una vez al d&#237;a en dosis de 5 y 2&#44;5<span class="elsevierStyleHsp" style=""></span>&#956;g con respecto al tiotropio HandiHaler<span class="elsevierStyleSup">&#174;</span> 18<span class="elsevierStyleHsp" style=""></span>&#956;g&#46; Este an&#225;lisis post-hoc reuni&#243; datos de todos los brazos de tratamiento para evaluar la mortalidad&#44; las exacerbaciones&#44; los acontecimientos card&#237;acos y los acontecimientos adversos graves &#40;AAG&#41; entre ambas regiones&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Al inicio del estudio&#44; los pacientes reclutados en Am&#233;rica Latina &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;000&#41; versus RdM &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16&#46;116&#41; eran de mayor edad&#44; con m&#225;s paquetes&#47;a&#241;o de consumo de tabaco en sus antecedentes y m&#225;s exacerbaciones&#44; pero menos antecedentes card&#237;acos&#46; En este an&#225;lisis&#44; los pacientes de Latinoam&#233;rica versus RdM ten&#237;an un mayor riesgo de muerte &#40;raz&#243;n de riesgo &#91;HR&#93; intervalo de confianza del 95&#37; &#91;IC 95&#37;&#93;&#58; 1&#44;52 &#91;1&#44;24-1&#44;86&#93;&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41; y de exacerbaci&#243;n moderada a grave &#40;HR &#91;IC 95&#37;&#93;&#58; 1&#44;29 &#91;1&#44;18-1&#44;41&#93;&#59; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;0001&#41;&#44; pero menor riesgo de exacerbaci&#243;n grave &#40;HR &#91;IC 95&#37;&#93;&#58; 0&#44;82 &#91;0&#44;68-0&#44;98&#93;&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;0333&#41;&#46; Las tasas de AAG en Latinoam&#233;rica fueron m&#225;s bajas frente al RdM &#40;tasa de incidencia &#91;IRR&#93; &#91;IC 95&#37;&#93;&#58; 0&#44;82 &#91;0&#44;72-0&#44;92&#93;&#41;&#44; incluidos los trastornos card&#237;acos &#40;IRR &#91;IC 95&#37;&#93;&#58; 0&#44;68 &#91;0&#44;48-0&#44;97&#93;&#41;&#46; El riesgo de acontecimientos cardiovasculares adversos mayores fue similar &#40;HR &#91;IC 95&#37;&#93;&#58; 0&#44;99 &#91;0&#44;71-1&#44;40&#93;&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;9677&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Los pacientes de TIOSPIR<span class="elsevierStyleSup">&#174;</span> en Latinoam&#233;rica tuvieron un mayor riesgo de muerte y de exacerbaci&#243;n moderada a grave&#44; pero un menor riesgo de exacerbaci&#243;n grave que aquellos en el RdM&#46; Las diferencias geogr&#225;ficas pueden afectar los resultados en los ensayos de la EPOC&#46;</p></span>"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Time to death by region and according to baseline characteristics &#40;vital status analysis&#41;&#46;</p> <p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Data were included if the death occurred up until the end of the study&#46;</p> <p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">BL&#44; baseline&#59; BMI&#44; body mass index&#59; CI&#44; confidence interval&#59; COPD&#44; chronic obstructive pulmonary disease&#59; GOLD&#44; Global Initiative for Chronic Obstructive Lung Disease&#59; HR&#44; hazard ratio&#59; ICS&#44; inhaled corticosteroid&#59; LABA&#44; long-acting &#946;<span class="elsevierStyleInf">2</span>-agonist&#59; RoW&#44; rest of the world&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0015"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
            "Alto" => 1049
            "Ancho" => 1651
            "Tamanyo" => 168884
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Time to first moderate-to-severe exacerbation by region &#40;on-treatment analysis&#41;&#46;</p> <p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Events were counted from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 day&#46;</p> <p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">COPD&#44; chronic obstructive pulmonary disease&#59; RoW&#44; rest of the world&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "fig0020"
        "etiqueta" => "Fig&#46; 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr4.jpeg"
            "Alto" => 2369
            "Ancho" => 2893
            "Tamanyo" => 564120
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">Time to first moderate-to-severe COPD exacerbation by region and according to baseline characteristics &#40;on-treatment analysis&#41;&#46;</p> <p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Events were counted from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 day&#46;</p> <p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">BL&#44; baseline&#59; BMI&#44; body mass index&#59; CI&#44; confidence interval&#59; COPD&#44; chronic obstructive pulmonary disease&#59; GOLD&#44; Global Initiative for Chronic Obstructive Lung Disease&#59; HR&#44; hazard ratio&#59; ICS&#44; inhaled corticosteroid&#59; LABA&#44; long-acting &#946;<span class="elsevierStyleInf">2</span>-agonist&#59; RoW&#44; rest of the world&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "fig0025"
        "etiqueta" => "Fig&#46; 5"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr5.jpeg"
            "Alto" => 1044
            "Ancho" => 1658
            "Tamanyo" => 153088
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Time to first severe exacerbation &#40;hospitalization&#41; by region &#40;on-treatment analysis&#41;&#46;</p> <p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Events were counted from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 day&#46;</p> <p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">COPD&#44; chronic obstructive pulmonary disease&#59; RoW&#44; rest of the world&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "fig0030"
        "etiqueta" => "Fig&#46; 6"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr6.jpeg"
            "Alto" => 2400
            "Ancho" => 2917
            "Tamanyo" => 460204
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0120" class="elsevierStyleSimplePara elsevierViewall">Time to first severe COPD exacerbation by region adjusted for relevant covariates<span class="elsevierStyleSup">a</span> &#40;on-treatment analysis&#41;&#46;</p> <p id="spar0125" class="elsevierStyleSimplePara elsevierViewall">Events were counted from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 day&#46;</p> <p id="spar0130" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">a</span>Adjusted for age&#44; FEV<span class="elsevierStyleInf">1</span>&#37; predicted&#44; gender&#44; exacerbation history&#44; smoking history &#40;pack-years&#41;&#44; BMI&#44; history of cardiac disorders&#44; myocardial infarction&#44; coronary artery disease&#47;ischaemic heart disease&#44; cardiac arrhythmia&#44; heart failure &#40;class I&#8211;IV&#41;&#44; and stroke&#47;transient ischemic attack&#46; Patients with missing covariates &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6 for Latin America and <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>45 for RoW&#41; are excluded&#46;</p> <p id="spar0135" class="elsevierStyleSimplePara elsevierViewall">BL&#44; baseline&#59; BMI&#44; body mass index&#59; CI&#44; confidence interval&#59; COPD&#44; chronic obstructive pulmonary disease&#59; FEV<span class="elsevierStyleInf">1</span>&#44; forced expiratory volume in 1 second&#59; GOLD&#44; Global Initiative for Chronic Obstructive Lung Disease&#59; HR&#44; hazard ratio&#59; ICS&#44; inhaled corticosteroid&#59; LABA&#44; long-acting &#946;<span class="elsevierStyleInf">2</span>-agonist&#59; RoW&#44; rest of the world&#46;</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "fig0035"
        "etiqueta" => "Fig&#46; 7"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr7.jpeg"
            "Alto" => 1013
            "Ancho" => 1611
            "Tamanyo" => 146216
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0140" class="elsevierStyleSimplePara elsevierViewall">Time to first MACE by region &#40;on-treatment analysis&#41;&#46;</p> <p id="spar0145" class="elsevierStyleSimplePara elsevierViewall">Events were counted from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>30 days&#46;</p> <p id="spar0150" class="elsevierStyleSimplePara elsevierViewall">MACE includes stroke&#44; transient ischaemic attack&#44; MI&#44; sudden death&#44; cardiac death&#44; sudden cardiac death&#44; or fatal event in SOCs for cardiac and vascular disorders&#46;</p> <p id="spar0155" class="elsevierStyleSimplePara elsevierViewall">SOCs were defined according to MedDRA and PT&#46;</p> <p id="spar0160" class="elsevierStyleSimplePara elsevierViewall">MACE&#44; major adverse cardiovascular event&#59; MedDRA&#44; Medical Dictionary for Regulatory Activities&#59; MI&#44; myocardial infarction&#59; PT&#44; preferred term&#59; RoW&#44; rest of the world&#59; SOC&#44; system organ class&#46;</p>"
        ]
      ]
      7 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0170" class="elsevierStyleSimplePara elsevierViewall">Patients with missing baseline characteristics are not shown&#46;</p><p id="spar0175" class="elsevierStyleSimplePara elsevierViewall">Cardiac history was defined as history of MI&#44; CAD&#47;IHD&#44; cardiac arrhythmia&#44; or heart failure&#46; Any CV medication includes &#946;-blockers&#44; calcium channel blockers&#44; cardiac glycosides &#40;digoxin&#41;&#44; angiotensin-converting enzyme inhibitors&#44; angiotensin receptor blockers&#44; nitrates&#44; anti-arrhythmics class I or III &#40;sodium or potassium channel blockers&#41;&#44; adenosine&#44; acetylsalicylic acid&#44; anticoagulants &#40;vitamin K antagonists&#44; direct thrombin inhibitors&#44; and factor Xa inhibitors&#41;&#44; and antiplatelets&#46;</p><p id="spar0180" class="elsevierStyleSimplePara elsevierViewall">BD&#44; bronchodilator&#59; BMI&#44; body mass index&#59; CAD&#44; coronary artery disease&#59; COPD&#44; chronic obstructive pulmonary disease&#59; CV&#44; cardiovascular&#59; FEV<span class="elsevierStyleInf">1</span>&#44; forced expiratory volume in 1 second&#59; GOLD&#44; Global Initiative for Chronic Obstructive Lung Disease&#59; ICS&#44; inhaled corticosteroids&#59; IHD&#44; ischaemic heart disease&#59; LABA&#44; long-acting &#946;<span class="elsevierStyleInf">2</span>-agonist&#59; LAMA&#44; long-acting muscarinic antagonist&#59; MI&#44; myocardial infarction&#59; mMRC&#44; Modified Medical Research Council&#59; RoW&#44; rest of the world&#59; SD&#44; standard deviation&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Characteristic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Latin America &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1000&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">RoW &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>116&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">P</span>-value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Male&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">687 &#40;68&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">11<span class="elsevierStyleHsp" style=""></span>550 &#40;71&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0437&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Age&#44; n &#40;&#37;&#41;</span></td><td class="td" title="table-entry  " rowspan="4" align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#60;60 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">225 &#40;22&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4538 &#40;28&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>60&#8211;&#60;70 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">377 &#40;37&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6325 &#40;39&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#8805;70 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">398 &#40;39&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5253 &#40;32&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">BMI&#44; kg&#47;m</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">2</span></span><span class="elsevierStyleItalic">&#44; n &#40;&#37;&#41;</span></td><td class="td" title="table-entry  " rowspan="5" align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#61;</span><span class="elsevierStyleHsp" style=""></span>&#46;0061</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Underweight&#44; BMI<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>18&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">60 &#40;6&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1038 &#40;6&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Normal&#44; 18&#46;5<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>BMI<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">434 &#40;43&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6252 &#40;38&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Pre-obese&#44; 25<span class="elsevierStyleHsp" style=""></span>&#8804;<span class="elsevierStyleHsp" style=""></span>BMI<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">321 &#40;32&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5188 &#40;32&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Obese&#44; BMI<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>30&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">185 &#40;18&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3638 &#40;22&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Duration of COPD&#44; years&#44; mean &#40;SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#46;9 &#40;5&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7&#46;5 &#40;6&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;1064&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Smoking history&#44; pack-years&#44; mean &#40;SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&#46;1 &#40;28&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">43&#46;5 &#40;24&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Current smoker&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">207 &#40;20&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6312 &#40;39&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Post-BD FEV</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">1</span></span><span class="elsevierStyleItalic">&#44; l&#44; mean &#40;SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;24 &#40;0&#46;46&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;35 &#40;0&#46;48&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Post-BD FEV</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">1</span></span><span class="elsevierStyleItalic">&#44; &#37; of predicted value&#44; mean &#40;SD&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">47&#46;0 &#40;14&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">48&#46;4 &#40;13&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">GOLD stage&#44; n &#40;&#37;&#41;</span></td><td class="td" title="table-entry  " rowspan="4" align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0020</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>I<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>II&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">465 &#40;46&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7727 &#40;47&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>III&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">397 &#40;39&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6449 &#40;40&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>IV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">130 &#40;13&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1712 &#40;10&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">mMRC scale&#44; n &#40;&#37;&#41;</span></td><td class="td" title="table-entry  " rowspan="4" align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0471</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">102 &#40;10&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1303 &#40;8&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">354 &#40;35&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6020 &#40;37&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#62;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">542 &#40;54&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8773 &#40;54&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">History of cardiac disorder&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">182 &#40;18&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4287 &#40;26&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">History of MI&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">38 &#40;3&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">988 &#40;6&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0026&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">History of CAD&#47;IHD&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">50 &#40;5&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2544 &#40;15&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">History of cardiac arrhythmia&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">120 &#40;12&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1705 &#40;10&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#61;</span><span class="elsevierStyleHsp" style=""></span>&#46;1597&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">History of heart failure&#44; class I&#8211;IV&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">21 &#40;2&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1317 &#40;8&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">Number of COPD exacerbations treated in last year&#44; n &#40;&#37;&#41;</span></td><td class="td" title="table-entry  " rowspan="4" align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">385 &#40;38&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8434 &#40;52&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">384 &#40;38&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4492 &#40;27&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>&#62;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">230 &#40;23&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3179 &#40;19&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Sputum-producing cough &#62;3</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mo for 2 years&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">579 &#40;58&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">10<span class="elsevierStyleHsp" style=""></span>307 &#40;64&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Any pulmonary medication&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">927 &#40;92&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">14<span class="elsevierStyleHsp" style=""></span>573 &#40;90&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0170&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">LAMA&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">242 &#40;24&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7781 &#40;48&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top"><span class="elsevierStyleItalic">ICS&#44; LABA&#44; or both&#44; n &#40;&#37;&#41;</span></td><td class="td" title="table-entry  " rowspan="5" align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LABA &#40;but not ICS&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">81 &#40;8&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1625 &#40;10&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>ICS &#40;but not LABA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">126 &#40;12&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1105 &#40;6&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>LABA and ICS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">566 &#40;56&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8306 &#40;51&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Neither &#40;ICS nor LABA&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">227 &#40;22&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5080 &#40;31&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Any CV medication&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">447 &#40;44&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8306 &#40;51&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top"><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#60;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;</span>0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Latin America &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1000&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">RoW &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>116&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Latin America vs RoW&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleBold">&#40;A&#41; Death</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Patients with deaths&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100 &#40;10&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1200 &#40;7&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Median time to death&#44; days</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;without additional covariates&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;52 &#40;1&#46;24&#8211;1&#46;86&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;with additional covariates&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;37 &#40;1&#46;11&#8211;1&#46;69&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0031&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleBold">&#40;B&#41; Moderate-to-severe exacerbation</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Patients with moderate-to-severe exacerbations&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">548 &#40;54&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7647 &#40;47&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Total number of moderate-to-severe exacerbations&#44; n</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1278&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">17<span class="elsevierStyleHsp" style=""></span>815&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Median time to moderate-to-severe exacerbation&#44; days</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">536&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">779&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Estimated annual rate&#44; mean &#40;95&#37; CI&#41;&#44; and RR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;without additional covariates&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;71 &#40;0&#46;65&#8211;0&#46;78&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;57 &#40;0&#46;56&#8211;0&#46;58&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;25 &#40;1&#46;13&#8211;1&#46;38&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Estimated annual rate&#44; mean &#40;95&#37; CI&#41;&#44; and RR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;with additional covariates&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;59 &#40;0&#46;52&#8211;0&#46;68&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;55 &#40;0&#46;50&#8211;0&#46;61&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;07 &#40;0&#46;97&#8211;1&#46;18&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;1650&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;without additional covariates&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;29 &#40;1&#46;18&#8211;1&#46;41&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;with additional covariates&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;13 &#40;1&#46;03&#8211;1&#46;23&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0081&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleBold">&#40;C&#41; Severe exacerbation</span><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Patients with severe exacerbations&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">114 &#40;11&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2392 &#40;14&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Total number of severe exacerbations&#44; n</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">156&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3660&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Median time to first severe exacerbation&#44; days</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Estimated annual rate&#44; mean &#40;95&#37; CI&#41;&#44; and RR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;without additional covariates&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;09 &#40;0&#46;07&#8211;0&#46;11&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;12 &#40;0&#46;12&#8211;0&#46;13&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;76 &#40;0&#46;61&#8211;0&#46;94&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0111&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Estimated annual rate&#59; mean &#40;95&#37; CI&#41;&#44; and RR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;with additional covariates&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;08 &#40;0&#46;06&#8211;0&#46;10&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;12 &#40;0&#46;10&#8211;0&#46;15&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;62 &#40;0&#46;50&#8211;0&#46;77&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;without additional covariates&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;82 &#40;0&#46;68&#8211;0&#46;98&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;0333&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;with additional covariates&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;67 &#40;0&#46;55&#8211;0&#46;81&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;0001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleBold">&#40;D&#41; MACE</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a><span class="elsevierStyleBold">and fatal MACE</span><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Patients with MACE&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">35 &#40;3&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">613 &#40;3&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;without additional covariates&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;99 &#40;0&#46;71&#8211;1&#46;40&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;9677&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;with additional covariates&#41;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;01 &#40;0&#46;71&#8211;1&#46;42&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#61;</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#46;9633</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Patients with fatal MACE&#44; n &#40;&#37;&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24 &#40;2&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">308 &#40;1&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>HR &#40;95&#37; CI&#41;&#59; <span class="elsevierStyleItalic">P</span>-value &#40;without additional covariates&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#46;41 &#40;0&#46;93&#8211;2&#46;13&#41;&#59;<br><span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;1082&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Vital status analysis &#40;data were included if the death occurred up until the end of the study&#41;&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">On-treatment analysis &#40;events were counted from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 day&#41;&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">On-treatment analysis &#40;from randomization to drug stop date<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>30 days&#41;&#46;</p>"
            ]
            3 => array:3 [
              "identificador" => "tblfn0020"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Adjusted for age&#44; FEV<span class="elsevierStyleInf">1</span>&#37; predicted&#44; gender&#44; exacerbation history&#44; smoking history &#40;pack-years&#41;&#44; body mass index&#44; and history of cardiac disorders&#44; myocardial infarction&#44; coronary artery disease&#47;ischaemic heart disease&#44; cardiac arrhythmia&#44; heart failure &#40;class I&#8211;IV&#41;&#44; and stroke&#47;transient ischemic attack&#46; Patients with missing covariates &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6 for Latin America and <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>45 for RoW&#41; are excluded&#46;</p> <p class="elsevierStyleNotepara" id="npar0025">CI&#44; confidence interval&#59; COPD&#44; chronic obstructive pulmonary disease&#59; FEV<span class="elsevierStyleInf">1</span>&#44; forced expiratory volume in 1 second&#59; HR&#44; hazard ratio&#59; MACE&#44; major adverse cardiovascular events&#59; RoW&#44; rest of the world&#59; RR&#44; rate ratio&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0185" class="elsevierStyleSimplePara elsevierViewall">Number of&#44; and time to&#58; &#40;A&#41; deaths&#44;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> &#40;B&#41; moderate-to-severe exacerbations&#44;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> &#40;C&#41; severe &#40;hospitalized&#41; exacerbations&#44;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> and &#40;D&#41; MACE<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> and fatal MACE<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> by region&#46;</p>"
        ]
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        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0200" class="elsevierStyleSimplePara elsevierViewall">CI&#44; confidence interval&#59; COPD&#44; chronic obstructive pulmonary disease&#59; IRR&#44; incidence rate ratio&#59; RoW&#44; rest of the world&#46;</p>"
          "tablatextoimagen" => array:1 [
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">n</span> &#40;incidence rate&#47;100 patient-years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Latin America &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1000&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">RoW &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16<span class="elsevierStyleHsp" style=""></span>116&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Latin America vs RoW IRR &#40;95&#37; CI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Patients with death due to any cause</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">100 &#40;4&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1200 &#40;3&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;49 &#40;1&#46;21&#8211;1&#46;82&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="4" align="left" valign="top"><span class="elsevierStyleBold">Adjudicated causes of death</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Cardiac disorders</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;0&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">61 &#40;0&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;46 &#40;0&#46;59&#8211;3&#46;64&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Gastrointestinal disorders</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;0&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27 &#40;0&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;30 &#40;1&#46;27&#8211;8&#46;58&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">General disorders and administration site conditions</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">25 &#40;1&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">294 &#40;0&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;52 &#40;1&#46;01&#8211;2&#46;28&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Death&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;0&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">90 &#40;0&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;78 &#40;0&#46;90&#8211;3&#46;54&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Sudden cardiac death&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">9 &#40;0&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">79 &#40;0&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;03 &#40;1&#46;02&#8211;4&#46;05&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Sudden death&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">7 &#40;0&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">121 &#40;0&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;03 &#40;0&#46;48&#8211;2&#46;21&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hepatobiliary disorders</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;57 &#40;0&#46;42&#8211;30&#46;53&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Infections and infestations</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12 &#40;0&#46;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">90 &#40;0&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;38 &#40;1&#46;30&#8211;4&#46;34&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Injury&#44; poisoning&#44; and procedural complications</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">37 &#40;0&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;48 &#40;0&#46;07&#8211;3&#46;51&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Neoplasms&#58; benign&#44; malignant&#44; and unspecified</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">17 &#40;0&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">287 &#40;0&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;06 &#40;0&#46;65&#8211;1&#46;72&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Nervous system disorders</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3 &#40;0&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">39 &#40;0&#46;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;37 &#40;0&#46;42&#8211;4&#46;44&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Psychiatric disorders</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;97 &#40;0&#46;36&#8211;24&#46;69&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Respiratory&#44; thoracic&#44; and mediastinal disorders</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">29 &#40;1&#46;4&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">340 &#40;0&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;52 &#40;1&#46;04&#8211;2&#46;22&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>COPD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">27 &#40;1&#46;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">315 &#40;0&#46;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;53 &#40;1&#46;03&#8211;2&#46;26&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Vascular disorders</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">12 &#40;0&#46;0&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;49 &#40;0&#46;19&#8211;11&#46;43&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0195" class="elsevierStyleSimplePara elsevierViewall">Adjudicated causes of death by region &#40;vital status analysis&#41;&#46;</p>"
        ]
      ]
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        "tipo" => "MULTIMEDIAECOMPONENTE"
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        "mostrarDisplay" => true
        "Ecomponente" => array:2 [
          "fichero" => "mmc1.docx"
          "ficheroTamanyo" => 14094
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:28 [
            0 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Worldwide burden of COPD in high- and low-income countries&#46; Part II&#46; Burden of chronic obstructive lung disease in Latin America&#58; the PLATINO study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46;M&#46; Menezes"
                            1 => "R&#46; Perez-Padilla"
                            2 => "P&#46;C&#46; Hallal"
                            3 => "J&#46;R&#46; Jardim"
                            4 => "A&#46; Muino"
                            5 => "M&#46;V&#46; Lopez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Int J Tuberc Lung Dis"
                        "fecha" => "2008"
                        "volumen" => "12"
                        "numero" => "Suppl&#46; 7"
                        "paginaInicial" => "709"
                        "paginaFinal" => "712"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18544192"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Global burden of COPD&#58; systematic review and meta-analysis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "R&#46;J&#46; Halbert"
                            1 => "J&#46;L&#46; Natoli"
                            2 => "A&#46; Gano"
                            3 => "E&#46; Badamgarav"
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Journal Information
Vol. 54. Issue 3.
Pages 140-148 (March 2018)
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Vol. 54. Issue 3.
Pages 140-148 (March 2018)
Original Article
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Demographic Characteristics and Clinical Outcomes in Patients from Latin America Versus the Rest of the World: A TIOSPIR® Post-Hoc Analysis
Características demográficas y resultados clínicos en pacientes de Latinoamérica respecto al resto del mundo: un análisis post-hoc de TIOSPIR®
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Antonio Anzuetoa,
Corresponding author
anzueto@uthscsa.edu

Corresponding author.
, Peter M.A. Calverleyb, Achim Muellerc, Norbert Metzdorfd, Michaela Haenseld, José R. Jardime, Emilio Pizzichinif, Horacio Giraldog, Alejandra Ramirez-Venegash, Eduardo R. Giugnoi
a Pulmonary/Critical Care, University of Texas and South Texas Veterans Health Care System, San Antonio, TX, USA
b Clinical Science Centre, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK
c Biostatistics and Data Sciences Europe, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
d Respiratory Medicine, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany
e Respiratory Division, Federal University of São Paulo, São Paulo, Brazil
f The Federal University of Santa Catarina, Florianópolis, Brazil
g Almirante Colón Medical Center, Clínica del Country, Bogotá, Colombia
h Tobacco Smoking and COPD Research Department, National Institute of Respiratory Diseases, Mexico City, Mexico
i Hospital Zonal Especializado de Agudos y Crónicos “Dr. Antonio Cetrángolo”, Buenos Aires, Argentina
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Tables (3)
Table 1. Patient baseline characteristics by region.
Table 2. Number of, and time to: (A) deaths,a (B) moderate-to-severe exacerbations,b (C) severe (hospitalized) exacerbations,b and (D) MACEc and fatal MACEa by region.
Table 3. Adjudicated causes of death by region (vital status analysis).
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Additional material (1)
Abstract
Introduction

Geographical variations may impact outcomes in chronic obstructive pulmonary disease (COPD). We evaluated differences in baseline characteristics and outcomes between patients enrolled in Latin America compared with the rest of the world (RoW) in the TIOtropium Safety and Performance In Respimat® (TIOSPIR®) trial.

Methods

TIOSPIR®, a 2–3-year, randomized, double-blind trial (n=17116; treated set), compared safety and efficacy of once-daily tiotropium Respimat® 5 and 2.5μg with tiotropium HandiHaler® 18μg. This post-hoc analysis pooled data from all treatment arms to assess mortality, exacerbations, cardiac events, and serious adverse events (SAEs) between both regions.

Results

At baseline, patients enrolled in Latin America (n=1000) versus RoW (n=16116) were older, with higher pack-years of smoking history and more exacerbations, but less cardiac history. In this analysis, patients in Latin America versus RoW had an increased risk of death (hazard ratio [HR] [95% confidence interval (CI)]: 1.52 [1.24–1.86]; P<.0001) or moderate-to-severe exacerbation (HR [95% CI]: 1.29 [1.18–1.41]; P<.0001), but a lower risk of severe exacerbation (HR [95% CI]: 0.82 [0.68–0.98]; P=.0333). SAE rates in Latin America were lower versus RoW (incidence rate ratio [IRR] [95% CI]: 0.82 [0.72–0.92]), including cardiac disorders (IRR [95% CI]: 0.68 [0.48–0.97]). Risk of major adverse cardiovascular events were similar (HR [95% CI]: 0.99 [0.71–1.40]; P=.9677).

Conclusions

TIOSPIR® patients in Latin America had a higher risk of death or moderate-to-severe exacerbation, but a lower risk of severe exacerbation than those in RoW. Geographical differences may impact outcomes in COPD trials.

Keywords:
Latin America
COPD
Exacerbation
Mortality
TIOSPIR®
Resumen
Introducción

Las variaciones geográficas pueden afectar a los resultados en la enfermedad pulmonar obstructiva crónica (EPOC). Evaluamos las diferencias en las características basales y los resultados de los pacientes incluidos en Latinoamérica en comparación con el resto del mundo (RdM) en el ensayo TIOtropium Safety and Performance In Respimat® (TIOSPIR®).

Métodos

TIOSPIR®, es un estudio aleatorizado, doble ciego de 2-3 años de duración (n=17.116; conjunto tratado), comparó la seguridad y la eficacia del tiotropio Respimat® una vez al día en dosis de 5 y 2,5μg con respecto al tiotropio HandiHaler® 18μg. Este análisis post-hoc reunió datos de todos los brazos de tratamiento para evaluar la mortalidad, las exacerbaciones, los acontecimientos cardíacos y los acontecimientos adversos graves (AAG) entre ambas regiones.

Resultados

Al inicio del estudio, los pacientes reclutados en América Latina (n=1.000) versus RdM (n=16.116) eran de mayor edad, con más paquetes/año de consumo de tabaco en sus antecedentes y más exacerbaciones, pero menos antecedentes cardíacos. En este análisis, los pacientes de Latinoamérica versus RdM tenían un mayor riesgo de muerte (razón de riesgo [HR] intervalo de confianza del 95% [IC 95%]: 1,52 [1,24-1,86]; p<0,0001) y de exacerbación moderada a grave (HR [IC 95%]: 1,29 [1,18-1,41]; p<0,0001), pero menor riesgo de exacerbación grave (HR [IC 95%]: 0,82 [0,68-0,98]; p=0,0333). Las tasas de AAG en Latinoamérica fueron más bajas frente al RdM (tasa de incidencia [IRR] [IC 95%]: 0,82 [0,72-0,92]), incluidos los trastornos cardíacos (IRR [IC 95%]: 0,68 [0,48-0,97]). El riesgo de acontecimientos cardiovasculares adversos mayores fue similar (HR [IC 95%]: 0,99 [0,71-1,40]; p=0,9677).

Conclusiones

Los pacientes de TIOSPIR® en Latinoamérica tuvieron un mayor riesgo de muerte y de exacerbación moderada a grave, pero un menor riesgo de exacerbación grave que aquellos en el RdM. Las diferencias geográficas pueden afectar los resultados en los ensayos de la EPOC.

Palabras clave:
Latinoamérica
EPOC
Exacerbación
Mortalidad
TIOSPIR®
Full Text
Introduction

Chronic obstructive pulmonary disease (COPD) represents an enormous health burden worldwide. Its prevalence is relatively high in Latin America, affecting an estimated 14.3%1 of the population versus 9.2%2 in the rest of the world (RoW). A substantial proportion of Latin American patients had experienced an exacerbation (18.2%),3 and respiratory causes, including COPD, are amongst the leading cause of mortality in this region.4 Smoking is a behaviour that is seemingly ingrained in Latin American culture,5 with smokers from Latin America constituting 8%–10% of tobacco smokers globally.6 Solid fuels are used by 30%–75% of households7 (traditionally in rural areas8) and contribute to mortality rates similar to those observed in tobacco smokers.9 Management guidelines for COPD recognize that curbing the smoking epidemic10,11 and reducing exposure to pollutants10 are necessary to lower COPD risk in developing countries, but do not detail regional differences in risk, outcomes, or treatment options.

The TIOtropium Safety and Performance In Respimat® (TIOSPIR®) study demonstrated similar efficacy and safety profiles between tiotropium Respimat® (2.5 or 5μg) and tiotropium HandiHaler® 18μg, with respect to risk of mortality and risk of exacerbation.12 A recent TIOSPIR® subanalysis demonstrated similar mortality rates in Asian patients versus RoW. Although exacerbation rates were lower in Asia, a higher proportion of patients had severe exacerbations than in RoW.13

The purpose of this post-hoc analysis was to determine whether there are differences in the baseline characteristics, mortality, exacerbations, cardiac adverse event, and serious adverse event (SAE) outcomes of patients from Latin American geographical region versus RoW in the TIOSPIR® trial.

MethodsStudy design

TIOSPIR® (NCT01126437) was a large (N=17135), long-term (2–3-year), randomized, double-blind, parallel-group, double-dummy, event-driven trial in patients with COPD comparing the safety and efficacy of once-daily tiotropium (SPIRIVA® [Boehringer Ingelheim, Ingelheim am Rhein, Germany]) via Respimat® 5μg (2 inhalations of 2.5μg), and 2.5μg (2 inhalations of 1.25μg), or via HandiHaler® 18μg; 17116 patients constituted the as-treated population and were included in this analysis. The study design, detailed methods, and primary results were published previously.12,14

Study population

All participants had a confirmed diagnosis of COPD (forced expiratory volume in 1 second [FEV1] ≤70% predicted and FEV1/forced vital capacity ≤0.70), were aged ≥40 years, and had ≥10 pack-years of smoking history.14 Patients with concomitant cardiac diseases were included in the study, except those with recent (≤6 months) myocardial infarction (MI), severe arrhythmia, or a change in drug therapy within the previous year; or hospitalization for cardiac failure within the previous year.14 All usual background treatments for COPD, except other inhaled anticholinergics, were allowed.14

The geographical region of Latin America enrolled patients in Argentina, Brazil, Colombia, Guatemala, Mexico, Panama, and Peru.

Outcome measures

Outcomes of interest in this analysis were time to all-cause death, time to first moderate-to-severe or severe exacerbation, time to major adverse cardiovascular events (MACE) and fatal MACE, and SAEs for patients in Latin America versus RoW.

Assessments

An independent mortality adjudication committee, blinded to treatment assignments attributed the cause of each death.14 Non-fatal stroke and MI (included in MACE) were reported by study investigators and verified for classification accuracy by central reviewers who were blinded to treatment assignment.

Exacerbations were defined as the worsening of ≥2 major respiratory symptoms (dyspnoea, cough, sputum, chest tightness, or wheezing) for ≥3 days and requiring specified treatment changes. Moderate-to-severe exacerbations required a prescription for antibiotics, systemic corticosteroids, or both (with no hospitalization); severe exacerbations required hospitalization. The onset of exacerbation was defined as the onset of the first recorded symptom; the end of exacerbation was decided by the investigator, based on clinical judgment.

A composite endpoint of MACE was included in the analyses, comprising stroke, transient ischaemic attack (TIA), MI, sudden death, cardiac death, sudden cardiac death, or fatal event in the system organ classes (SOCs) for cardiac and vascular disorders. SOCs were defined according to the Medical Dictionary for Regulatory Activities standardizing attributions of AEs globally.

Statistical analysis

Based on similar efficacy and safety results among the tiotropium treatment arms in the primary analysis,12 data were pooled for this post-hoc exploratory analysis.

Baseline characteristics discriminating between patients in Latin America and RoW were identified and compared descriptively.

Hazard ratios (HRs) and 95% confidence intervals (CIs) for time to events by region were calculated using a Cox proportional hazards regression model without covariate adjustment, and displayed via Kaplan–Meier plots. A negative binomial regression model was used to estimate the number of exacerbations. HRs for time to death and time to moderate-to-severe exacerbation analyses, by region and baseline characteristics, are shown as forest plots. Additional analyses of time to death and moderate-to-severe exacerbation, severe exacerbations, and MACE were adjusted for covariates including age, post-bronchodilator FEV1% predicted, gender, exacerbation history, smoking history (pack-years), body mass index (BMI), and history of cardiac disorders, MI, coronary artery disease/ischaemic heart disease (CAD/IHD), cardiac arrhythmia, heart failure (class I–IV), and stroke/TIA.

Incidence rates, incidence rate ratios (IRRs), and 95% CIs for causes of death were calculated. SAEs are provided in the Supplementary Material.

For the mortality analysis (vital status), data were included if death occurred up until the study end date, irrespective of treatment discontinuation. For the exacerbation analysis (on-treatment), events were counted from randomization to drug stop date+1 day, and for MACE to drug stop date+30 days.

ResultsStudy population

Of the TIOSPIR® population, 1000 patients from Latin America and 16116 patients from RoW were included (Table 1). Total exposure to tiotropium was 1855 and 32229 patient-years for Latin America and RoW, respectively. A total of 228 (22.8%) patients from Latin America and 3689 (22.9%) patients from RoW discontinued prematurely from trial medication. Reasons for premature discontinuation were similar, and mainly due to AEs, with respiratory disorders (including COPD) being the most common AEs, followed by neoplasms, and infections and infestations.12 Vital status follow-up was complete for 99.1% and 99.8% of patients from Latin America and RoW, respectively.

Table 1.

Patient baseline characteristics by region.

Characteristic  Latin America (n=1000)  RoW (n=16116)  P-value 
Male, n (%)  687 (68.7)  11550 (71.7)  P=.0437 
Age, n (%)P<.0001
<60 years  225 (22.5)  4538 (28.2) 
60–<70 years  377 (37.7)  6325 (39.2) 
≥70 years  398 (39.8)  5253 (32.6) 
BMI, kg/m2, n (%)P=.0061
Underweight, BMI<18.5  60 (6.0)  1038 (6.4) 
Normal, 18.5BMI<25  434 (43.4)  6252 (38.8) 
Pre-obese, 25BMI<30  321 (32.1)  5188 (32.2) 
Obese, BMI30  185 (18.5)  3638 (22.6) 
Duration of COPD, years, mean (SD)  6.9 (5.4)  7.5 (6.2)  P=.1064 
Smoking history, pack-years, mean (SD)  48.1 (28.6)  43.5 (24.5)  P<.0001 
Current smoker, n (%)  207 (20.7)  6312 (39.2)  P<.0001 
Post-BD FEV1, l, mean (SD)  1.24 (0.46)  1.35 (0.48)  P<.0001 
Post-BD FEV1, % of predicted value, mean (SD)  47.0 (14.3)  48.4 (13.8)  P=.0021 
GOLD stage, n (%)P=.0020
I+II  465 (46.5)  7727 (47.9) 
III  397 (39.7)  6449 (40.0) 
IV  130 (13.0)  1712 (10.6) 
mMRC scale, n (%)P=.0471
102 (10.2)  1303 (8.1) 
354 (35.4)  6020 (37.4) 
>1  542 (54.2)  8773 (54.4) 
History of cardiac disorder, n (%)  182 (18.2)  4287 (26.6)  P<.0001 
History of MI, n (%)  38 (3.8)  988 (6.1)  P=.0026 
History of CAD/IHD, n (%)  50 (5.0)  2544 (15.8)  P<.0001 
History of cardiac arrhythmia, n (%)  120 (12.0)  1705 (10.6)  P=.1597 
History of heart failure, class I–IV, n (%)  21 (2.1)  1317 (8.2)  P<.0001 
Number of COPD exacerbations treated in last year, n (%)P<.0001
385 (38.5)  8434 (52.3) 
384 (38.4)  4492 (27.9) 
>1  230 (23.0)  3179 (19.7) 
Sputum-producing cough >3mo for 2 years, n (%)  579 (58.0)  10307 (64.0)  P=.0001 
Any pulmonary medication, n (%)  927 (92.7)  14573 (90.4)  P=.0170 
LAMA, n (%)  242 (24.2)  7781 (48.3)  P<.0001 
ICS, LABA, or both, n (%)P<.0001
LABA (but not ICS)  81 (8.1)  1625 (10.1) 
ICS (but not LABA)  126 (12.6)  1105 (6.9) 
LABA and ICS  566 (56.6)  8306 (51.5) 
Neither (ICS nor LABA)  227 (22.7)  5080 (31.5) 
Any CV medication, n (%)  447 (44.7)  8306 (51.5)  P<.0001 

Patients with missing baseline characteristics are not shown.

Cardiac history was defined as history of MI, CAD/IHD, cardiac arrhythmia, or heart failure. Any CV medication includes β-blockers, calcium channel blockers, cardiac glycosides (digoxin), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, nitrates, anti-arrhythmics class I or III (sodium or potassium channel blockers), adenosine, acetylsalicylic acid, anticoagulants (vitamin K antagonists, direct thrombin inhibitors, and factor Xa inhibitors), and antiplatelets.

BD, bronchodilator; BMI, body mass index; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; FEV1, forced expiratory volume in 1 second; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; IHD, ischaemic heart disease; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; MI, myocardial infarction; mMRC, Modified Medical Research Council; RoW, rest of the world; SD, standard deviation.

Baseline characteristics

At baseline, patients enrolled in Latin America were comparatively older (higher proportion of patients aged ≥70 years), and had higher mean pack-years of smoking history than those in RoW, although a lower percentage were current smokers (Table 1). A higher proportion of patients in Latin America had COPD exacerbation in the year prior to the trial than those in RoW. Latin American patients were more likely to have very severe COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stage IV) versus RoW (Table 1). Fewer Latin American patients had a history of cardiac disorders, or were receiving cardiovascular medication at baseline versus RoW (Table 1). The proportions of patients receiving long-acting muscarinic antagonist (LAMA) or long-acting β2-agonist (LABA) at baseline were lower in Latin America than in RoW; however, they were more likely to receive inhaled corticosteroids (ICS) (with or without LABA) (Table 1).

Mortality

During the study, a greater proportion of patients died in the Latin American population (n=100 [10.0%]) versus RoW (n=1200 [7.4%]) (Table 2A). Analysis of time to death confirmed that patients in Latin America had a higher risk of death than those in RoW (HR [95% CI]: 1.52 [1.24–1.86]) (Table 2A; Fig. 1). This was also true when the analysis of time to death was adjusted for age, gender, FEV1% predicted, exacerbation history, smoking history (pack-years), BMI, history of cardiac disorders, MI, CAD/IHD, cardiac arrhythmia, heart failure (class I–IV), and stroke/TIA (HR [95% CI]: 1.37 [1.11–1.69]) (Table 2A).

Table 2.

Number of, and time to: (A) deaths,a (B) moderate-to-severe exacerbations,b (C) severe (hospitalized) exacerbations,b and (D) MACEc and fatal MACEa by region.

  Latin America (n=1000)  RoW (n=16116)  Latin America vs RoW 
(A) Deatha
Patients with deaths, n (%)  100 (10.0)  1200 (7.4)  – 
Median time to death, days  –  –  – 
HR (95% CI); P-value (without additional covariates)  –  –  1.52 (1.24–1.86);
P<.0001 
HR (95% CI); P-value (with additional covariates)d  –  –  1.37 (1.11–1.69);
P=.0031 
(B) Moderate-to-severe exacerbationb
Patients with moderate-to-severe exacerbations, n (%)  548 (54.8)  7647 (47.4)  – 
Total number of moderate-to-severe exacerbations, n  1278  17815  – 
Median time to moderate-to-severe exacerbation, days  536